Antibacterial compositions

ABSTRACT

Compositions comprising N-sulfanilyl-1-ethylcytosine and a sulfonamide potentiator, which are useful as antibacterial agents, are described.

This is a division of application Ser. No. 794,422, filed May 6, 1977now U.S. Pat. No. 4,089,950, which in turn is a division of applicationSer. No. 676,581, filed Apr. 13, 1976, now U.S. Pat. No. 4,039,667,issued Aug. 2, 1977, which in turn is a division of application Ser. No.529,179, filed Dec. 3, 1974, now U.S. Pat. No. 3,996,357, issued Dec. 7,1976.

BRIEF SUMMARY OF THE INVENTION

The invention relates to antibacterial compositions comprisingN-sulfanilyl-1-ethylcytosine, which has the formula ##STR1## or apharmaceutically acceptable salt thereof with a strong base and asulfonamide potentiator, for example, a 2,4-diamino-5-benzylpyrimidinepotentiator.

DETAILED DESCRIPTION OF THE INVENTION

The antibacterial compositions of the invention contain the sulfonamideof the formula ##STR2## or a pharmaceutically acceptable salt thereofwith a strong base and a sulfonamide potentiator.

The compound of formula I is a known compound and has antibacterialactivity. Unexpectedly, it has been found that by the addition of asulfonamide potentiator, the chemotherapeutic activity of the compoundof formula I and its salts, especially the antibacterial activity inurine, can be surprisingly increased to a significant extent.

Particularly suitable sulfonamide potentiators in accordance with theinvention are 2,4-diamino-5-benzyl-pyrimidines of the formula ##STR3##

wherein R¹ is lower alkoxy, R² is lower alkoxy and R³ is amino, (loweralkyl)amino, di(lower alkyl)amino or lower alkoxy,

Or pharmaceutically acceptable acid addition salts thereof.

As used herein, the terms "lower alkyl" and "lower alkoxy" denotestraight-chain and branched-chain alkyl and alkoxy, respectively, whichpreferably contain from 1 to 7 carbon atoms, most preferably, from 1 to4 carbon atoms, such as methyl, methoxy, ethyl, ethoxy, propyl, propoxy,isopropyl, isopropoxy, butyl, isobutyl, tert.-butyl, isobutoxy,tert.-butoxy or the like. A preferred lower alkoxy is methoxy.Particularly preferred 2,4-diamino-5-benzyl-pyrimidines of formula IIare 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine and2,4-diamino-5-(4-amino-3,5-dimethoxybenzyl)-pyrimidine.

The 2,4-diamino-5-benzyl-pyrimidines of formula II, insofar as they arenot known, can be prepared either in a known manner or, for example, bychlorinating or brominating a compound of the formula ##STR4## whereinR⁴ is amino, (lower alkyl)amino or di(lower alkyl)-amino and R¹ and R²are as previously described,

in a known manner and reacting the resulting halo compound with ammonia.The reaction with ammonia is conveniently carried out in alkanolic,preferably methanolic solution, at a temperature in the range of fromabout 80° C. to about 200° C., preferably in the range of from about100° C. to about 150° C. Since these temperatures are above the boilingpoint of methanol, the reaction is carried out in a closed system, forexample, in an autoclave.

Physiologically and pharmaceutically acceptable acid addition salts of2,4-diamino-5-benzyl-pyrimidines of formula II can be prepared usingconventional inorganic and organic acids, such as hydrochloric acid,sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid,succinic acid, malic acid, citric acid, tartaric acid, maleic acid,fumaric acid, methanesulfonic acid, p-toluene-sulfonic acid or the like.

As physiologically or pharmaceutically acceptable strong bases for thepreparation of salts of N-sulfanilyl-1-ethylcytosine of formula I therecan be used conventional inorganic and organic bases, for example,alkali metal hydroxides and alkanolamines such as ethanolamine, and thelike.

The weight ratio of sulfonamide to sulfonamide potentiator in theantibacterial compositions provided by the invention conveniently is inthe range of from about 1:1 to about 40:1, preferably 5:1. Theantibacterial compositions of the invention include not only mixtureswhich consist solely of the two active ingredients, namely, thesulfonamide and the sulfonamide potentiator, but also mixtures whichcontain one or more additional substances, for example, activeingredients.

The process provided by the invention for the preparation of theantibacterial compositions comprises mixing the sulfonamide of formula Iwith the sulfonamide potentiator ingredient. The sulfonamide and thesulfonamide potentiator is conveniently used in a weight ratio of fromabout 1:1 to about 40:1, preferably 5:1. The process can be carried outin a known manner.

The antibacterial compositions provided by the invention, which possessgood tolerance or slight or low toxicity, are active againstgram-positive and gram-negative bacteria, such as coli and Proteusbacilli, Klebsiellae, Aerobacter, Enterococci, or the like. Theantibacterial compositions are particularly active, for example, againstEscherichia coli, Proteus vulgaris, Proteus mirabilis, Klebsiellapneumoniae, Aerobacter aerogenes and Streptococcus faecalis.Accordingly, the compositions of the invention are suitable forcombating and preventing bacterial infections, especially the so-calledcavity infections, such as infections of the urinary tract. Theantibacterial compositions of the invention can be administered orallyor parenterally.

When 200 mg/kg. of a 5:1 mixture of N-sulfanilyl-1-ethylcytosine and2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine were administeredorally to rats a very high order of activity was observed. The activity,measured in urine, of this combination against E. coli is, for example,92 times greater than that of 200 mg/kg. ofN-(5-nitro-2-furfuryliden)-1-amino-hydantoin and 203 times greater thanthat of the corresponding amount (namely 167 mg/kg.) of theunpotentiated N-sulfanilyl-1-ethylcytosine.

The antibacterial compositions provided by the invention can beadministered in the form of pharmaceutical preparations which contain anorganic or inorganic, inert carrier material suitable for oral orparenteral administration, for example, water, gelatin, gum arabic,lactose, starch, magnesium stearate, talc, vegetable oils,polyalkyleneglycols, or the like. The pharmaceutical preparations can bemade up in a solid form, for example, as tablets, dragees, suppositoriesor capsules, or in a liquid form, for example, as solutions, suspensionsor emulsions. The compositions may be sterilized and/or may containadjuvants such as preservatives, stabilizers, wetting agents,emulsifiers, salts for varying the osmotic pressure or buffers.

The preparation of the pharmaceutical preparations can be carried out ina known manner.

A suitable tablet can, for example, contain 400 mg. ofN-sulfanilyl-1-ethylcytosine and 80 mg. of2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine or it can, for example,contain 50% of each of these amounts. The dose administered daily canbe, or has to be, suited to individual requirements and can be variedwithin wide limits.

The following Examples further illustrate the invention.

EXAMPLE 1

Medicinal preparations containing N-sulfanilyl-1-ethylcytosine and2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine in a weight ratio of5:1 (active ingredient) can comprise the following:

    ______________________________________                                        a) Tablets:      Formulation A                                                                             Formulation B                                    ______________________________________                                        N-sulfanilyl-1-ethylcytosine                                                                   400 mg.     200 mg.                                          2,4-diamino-5-(3,4,5-tri-                                                     methoxybenzyl)pyrimidine                                                                       80 mg.      40 mg.                                           Mannitol         --          50 mg.                                           Lactose          30 mg.      50 mg.                                           Microcrystalline cellulose                                                                     120 mg.     147 mg.                                          Tylose            5 mg.       3 mg.                                           Talc             14 mg.       9 mg.                                           Magnesium stearate                                                                              1 mg.       1 mg.                                                            650 mg.     500 mg.                                          ______________________________________                                    

The active ingredients are mixed with a portion of the microcrystallinecellulose, lactose and, optionally, maize starch. The mixture isgranulated with an aqueous or alcoholic/aqueous Tylose solution anddried and, after the addition of the remaining ingredients, pressed intotablets.

    ______________________________________                                        b) Injection solution in 5 ml.                                                ampules:         Formulation A                                                                             Formulation B                                    ______________________________________                                        N-sulfanilyl-1-ethylcytosine                                                                   400.0 mg.   400.0 mg.                                        2,4-diamino-5-(3,4,5-trimethoxy-                                              benzyl)-pyrimidine                                                                             80.0 mg.     80.0 mg.                                        Sodium hydroxide 59.1 mg.    --                                               Diethanolamine   --          155.4 mg.                                        Water for injection purposes                                                  ad 5 ml.                                                                      ______________________________________                                    

The ampules are filled under nitrogen and sterilized in an autoclave at120° C.

    ______________________________________                                        c) Capsules:     Formulation A                                                                             Formulation B                                    ______________________________________                                        N-sulfanilyl-1-ethylcytosine                                                                   200.0 mg.   400.0 mg.                                        2,4-diamino-5-(3,4,5-tri-                                                     methoxybenzyl)-pyrimidine                                                                      40.0 mg.    80.0 mg.                                         Methylcellulose  2.5 mg.     5 mg.                                            Talc             4.0 mg.     8 mg.                                            Modified starch  7.5 mg.     15 mg.                                           Magnesium stearate                                                                             1.0 mg.     2 mg.                                                             255.0 mg.   510 mg.                                          ______________________________________                                    

The active ingredients are moistened with a methylcellulose solution andkneaded. The mass is then granulated, dried and sieved. A mixture of themodified starch, talc and magnesium stearate is mixed with thegranulate. Filling into interlocking gelatin capsules is carried out onan automatic capsule filling machine.

EXAMPLE 2

Medicinal preparations containing N-sulfanilyl-1-ethylcytosine and2,4-diamino-5-(4-amino-3,5-dimethoxybenzyl)-pyrimidine in a weight ratioof 5:1 (active ingredient) can comprise the following:

    ______________________________________                                        a) Tablets       Formulation A                                                                             Formulation B                                    ______________________________________                                        N-sulfanilyl-1-ethyl-                                                         cytosine         416.67 mg.  208.33 mg.                                       2,4-diamino-5-(4-amino-                                                       3,5-dimethoxybenzyl)-                                                         pyrimidine       83.33 mg.   41.67 mg.                                        Mannitol         30 mg.      30 mg.                                           Maize starch     50 mg.      30 mg.                                           Talc             18 mg.      9 mg.                                            Magnesium stearate                                                                             2 mg.       1 mg.                                                             600 mg.     320 mg.                                          ______________________________________                                    

The active ingredients are mixed with the mannitol and a portion of themaize starch, moistened with a maize starch paste and kneaded. The massis then granulated, dried and sieved and, after the addition of theremaining ingredients, can be pressed into tablets.

    ______________________________________                                        b) Capsules:     Formulation A                                                                             Formulation B                                    ______________________________________                                        N-sulfanilyl-1-ethyl-                                                         cytosine         416.67 mg.  208.33 mg.                                       2,4-diamino-5-(4-amino-                                                       3,5-dimethoxybenzyl)-                                                         pyrimidine       83.33 mg.   41.67 mg.                                        Hydroxypropyl methyl-                                                         cellulose        5 mg.       3 mg.                                            Modified starch  10 mg.      7 mg.                                            Talc             9 mg.       9 mg.                                            Magnesium stearate                                                                             1 mg.       1 mg.                                                             525 mg.     270 mg.                                          ______________________________________                                    

The active ingredient is moistened with an aqueous hydroxypropylmethylcellulose solution and kneaded. The mass is then granulated, driedand sieved and, after the addition of the remaining ingredients, isready for filling into capsules on an automatic capsule filling machine.

We claim:
 1. An antibacterial composition comprising the sulfonamideN-sulfanilyl-1-ethylcytosine or a pharmaceutically acceptable saltthereof with a strong base and the sulfonamide potentiator2,4-diamino-5-(4-amino-3,5-diethoxybenzyl)pyrimidine, wherein the weightratio of sulfonamide to sulfonamide potentiator is in the range of from1:1 to 40:1.
 2. A composition in accordance with claim 1, wherein theweight ratio of sulfonamide to sulfonamide potentiator is 5:1.